Rett syndrome (RTT) is a childhood neurobehavioral disorder caused by mutations in the methyI-CpG-binding protein 2 (MECP2) gene, which encodes a transcriptional repressor. RTT is characterized by mental retardation, seizures, stereotypic movements, breathing dysfunction and anxiety. MECP2 mutations also have been linked to juvenile onset schizophrenia and bipolar disorder. Our lab generated a model of RTT (the Mecp2308/Y mouse) that recapitulates features of RTT including anxiety. The overall hypothesis is that MECP2 mutation causes the misregulation of stress-response genes, leading to anxiety in RTT and Mecp2308/Y mice. To test this hypothesis, the anxiety phenotype of Mecp2308/Y mice will be characterized in detail using behavioral and physiologic tests. The molecular basis of their behavior will be investigated using enzyme linked immunosorbent assay (ELISA) and autoradiography to examine serotonin (5-HT) and 5-HT receptors, respectively, in the Mecp2308/Y mouse brain. Finally, pharmacologic manipulation of 5-HT receptors will be performed in an attempt to alleviate anxiety in these mice. These studies will aid in understanding the basis of anxiety in Mecp2308/Y mice and may lead to the appropriate treatment of this aspect of RTT.